INDICATIONS

DASATINIB is indicated for the treatment of adult patients with:

• Newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase
• Chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib
• Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy

DASATINIB is indicated for the treatment of pediatric patients 1 year of age and older with:

• Newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in combination with chemotherapy
• Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase

SUMMARY OF WARNINGS AND PRECAUTIONS

DASATINIB is associated with the following warnings and precautions: myelosuppression, bleeding-related events, fluid retention, cardiovascular toxicity, pulmonary arterial hypertension, QT prolongation, severe dermatologic reactions, tumor lysis syndrome, embryo-fetal toxicity, and hepatotoxicity.

IMPORTANT SAFETY INFORMATION

Myelosuppression:

Treatment with DASATINIB is associated with severe (NCI CTCAE Grade 3/4) thrombocytopenia, neutropenia, and anemia, which occur earlier and more frequently in patients with advanced phase CML or Ph+ ALL than in patients with chronic phase CML. Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities.

In patients with chronic phase CML, perform complete blood counts (CBCs) every 2 weeks for 12 weeks, then every 3 months thereafter, or as clinically indicated

• In patients with advanced phase CML or Ph+ ALL, perform CBCs weekly for the first 2 months and then monthly thereafter, or as clinically indicated
• In pediatric patients with Ph+ ALL treated with DASATINIB in combination with chemotherapy, perform CBCs prior to the start of each block of chemotherapy and as clinically indicated. During the consolidation blocks of chemotherapy, perform CBCs every 2 days until recovery
• Myelosuppression is generally reversible and usually managed by withholding DASATINIB temporarily and/or dose reduction
  • In clinical studies, myelosuppression may have also been managed by discontinuation of study therapy
  • Hematopoietic growth factor has been used in patients with resistant myelosuppression



Bleeding-Related Events:

DASATINIB can cause serious and fatal bleeding. In all CML or Ph+ ALL clinical studies, Grade ≥3 central nervous system (CNS) hemorrhages, including fatalities, occurred in <1% of patients receiving DASATINIB. The incidence of Grade 3/4 hemorrhage occurred in 5.8% of patients and generally required treatment interruptions and transfusions. The incidence of Grade 5 hemorrhage occurred in 0.4% of adult patients. The most frequent site of hemorrhage was gastrointestinal.

• Most bleeding events in clinical studies were associated with severe thrombocytopenia
• In addition to causing thrombocytopenia in human subjects, DASATINIB caused platelet dysfunction in vitro
• Concomitant medications that inhibit platelet function or anticoagulants may increase the risk of hemorrhage



Fluid Retention:

DASATINIB may cause fluid retention. After 5 years of follow-up in the randomized newly diagnosed chronic phase CML study (n=258), grade 3/4 fluid retention was reported in 5% of patients, including 3% of patients with grade 3/4 pleural effusion.




In adult patients with newly diagnosed or imatinib-resistant or -intolerant chronic phase CML, grade 3/4 fluid retention occurred in 6% of patients treated with DASATINIB at the recommended dose (n=548).




In patients with advanced phase CML or Ph+ ALL treated with DASATINIB at the recommended dose (n=304), grade 3/4 fluid retention was reported in 8% of patients, including grade 3/4 pleural effusion reported in 7% of patients.




In pediatric patients with chronic phase CML, cases of Grade 1 or 2 fluid retention were reported in 10.3% of patients.

• Patients who develop symptoms of pleural effusion or other fluid retention, such as new or worsened dyspnea on exertion or at rest, pleuritic chest pain, or dry cough should be evaluated promptly with a chest x-ray or additional diagnostic imaging as appropriate
• Fluid retention events were typically managed by supportive care measures that may include diuretics or short courses of steroids
• Severe pleural effusion may require thoracentesis and oxygen therapy
• Consider dose reduction or treatment interruption



Cardiovascular Toxicity:

DASATINIB can cause cardiac dysfunction. After 5 years of follow-up in the randomized, newly diagnosed chronic phase CML trial (n=258), the following cardiac adverse reactions occurred:



• Cardiac ischemic events (3.9% DASATINIB vs 1.6% imatinib), cardiac-related fluid retention (8.5% DASATINIB vs 3.9% imatinib), and conduction system abnormalities, most commonly arrhythmia and palpitations (7.0% DASATINIB vs 5.0% imatinib). Two cases (0.8%) of peripheral arterial occlusive disease occurred with imatinib and 2 (0.8%) transient ischemic attacks occurred with DASATINIB



Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.




Pulmonary Arterial Hypertension (PAH):

DASATINIB may increase the risk of developing PAH, which may occur any time after initiation, including after more than 1 year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation of DASATINIB.

• Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating DASATINIB and during treatment. If PAH is confirmed, DASATINIB should be permanently discontinued



QT Prolongation:

DASATINIB may increase the risk of prolongation of QTc in patients including those with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking antiarrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy.

• Correct hypokalemia or hypomagnesemia prior to and during DASATINIB administration



Severe Dermatologic Reactions:

Cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported in patients treated with DASATINIB.

• Discontinue permanently in patients who experience a severe mucocutaneous reaction during treatment if no other etiology can be identified



Tumor Lysis Syndrome (TLS):

TLS has been reported in patients with resistance to prior imatinib therapy, primarily in advanced phase disease.

• Due to potential for TLS, maintain adequate hydration, correct uric acid levels prior to initiating therapy with DASATINIB, and monitor electrolyte levels
• Patients with advanced stage disease and/or high tumor burden may be at increased risk and should be monitored more frequently



Embryo-Fetal Toxicity:

Based on limited human data, DASATINIB can cause fetal harm when administered to a pregnant woman. Hydrops fetalis, fetal leukopenia and fetal thrombocytopenia have been reported with maternal exposure to DASATINIB. Transplacental transfer of DASATINIB has been measured in fetal plasma and amniotic fluid at concentrations comparable to those in maternal plasma.

• Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with DASATINIB and for 30 days after the last dose



Effects on Growth and Development in Pediatric Patients:

In pediatric trials of DASATINIB in chronic phase CML after at least 2 years of treatment, adverse reactions associated with bone growth and development were reported in 5 (5.2%) patients, one of which was severe in intensity (Growth Retardation Grade 3). These 5 cases included cases of epiphyses delayed fusion, osteopenia, growth retardation, and gynecomastia. Of these 5 cases, 1 case of osteopenia and 1 case of gynecomastia resolved during treatment.




Monitor bone growth and development in pediatric patients.




Hepatotoxicity:

DASATINIB may result in hepatotoxicity as measured by elevation in bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase. Monitor transaminases at baseline and monthly or as clinically indicated during treatment. Reduce dose, withhold, or permanently discontinue DASATINIB based on severity. When combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Monitoring of hepatic function is recommended.




Lactation:

No data are available regarding the presence of DASATINIB in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. However, DASATINIB is present in the milk of lactating rats.

• Because of the potential for serious adverse reactions in nursing children from DASATINIB, breastfeeding is not recommended during treatment with DASATINIB and for 2 weeks after the last dose



Drug Interactions:

Effect of Other Drugs on DASATINIB:

• Strong CYP3A4 inhibitors: The coadministration with strong CYP3A inhibitors may increase DASATINIB concentrations. Increased DASATINIB concentrations may increase the risk of toxicity. Avoid concomitant use of strong CYP3A4 inhibitors. If concomitant administration of a strong CYP3A4 inhibitor cannot be avoided, consider a DASATINIB dose reduction
  • Grapefruit juice may increase plasma concentrations of DASATINIB and should be avoided
• Strong CYP3A4 inducers: The coadministration of DASATINIB with strong CYP3A inducers may decrease DASATINIB concentrations. Decreased DASATINIB concentrations may reduce efficacy. Consider alternative drugs with less enzyme induction potential. If concomitant administration of a strong CYP3A4 inducer cannot be avoided, consider a DASATINIB dose increase
  • St. John's wort may decrease plasma concentrations of DASATINIB and should be avoided
• Gastric Acid Reducing Agents: The coadministration of DASATINIB with a gastric acid reducing agent may decrease the concentrations of DASATINIB. Decreased DASATINIB concentrations may reduce efficacy Do not administer H₂ antagonists or proton pump inhibitors with DASATINIB. Consider the use of antacids in place of H₂ antagonists or proton pump inhibitors. Administer the antacid at least 2 hours prior to or 2 hours after the dose of DASATINIB. Avoid simultaneous administration of DASATINIB with antacidss.



Adverse Reactions:

The safety data reflects exposure to DASATINIB at doses tested in clinical studies (n=2712), including 324 adult patients with newly diagnosed chronic phase CML and 2388 adult patients with imatinib-resistant or -intolerant chronic or advanced phase Ph+ CML or Ph+ ALL.




The median duration of therapy in a total of 2712 DASATINIB-treated adult patients was 19.2 months (range 0-93.2 months). Median duration of therapy in:

• 1618 adult patients with chronic phase CML was 29 months (range 0-92.9 months)
• 324 patients in the newly diagnosed chronic phase CML trial was approximately 60 months
• 1094 adult patients with advanced phase CML or Ph+ ALL was 6.2 months (range 0-93.2 months)



In the overall population of 2712 DASATINIB-treated adult patients, 88% of patients experienced adverse reactions at some time and 19% experienced adverse reactions leading to treatment discontinuation.




Among the 1618 DASATINIB-treated patients with chronic phase CML, drug-related adverse reactions leading to discontinuation were reported in 329 (20.3%) patients.




In the newly diagnosed chronic phase CML trial, drug was discontinued for adverse reactions in 16% of the adult patients with a minimum of 60 months of follow-up. After a minimum of 60 months of follow-up, the cumulative discontinuation rate was 39%.




Among the 1094 DASATINIB-treated patients with advanced phase CML or Ph+ ALL, drug-related adverse reactions leading to discontinuation were reported in 191 (17.5%) patients.




Patients ≥65 years are more likely to experience the commonly reported adverse reactions of fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance, and more likely to experience the less frequently reported adverse reactions of abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema and weight decrease, and should be monitored closely.

• In newly diagnosed chronic phase CML patients:
  • Drug-related serious adverse reactions (SARs) were reported for 16.7% of DASATINIB-treated patients. Serious adverse reactions reported in ≥5% of patients included pleural effusion (5%)
  • The most common adverse reactions (≥15%) included myelosuppression, fluid retention, and diarrhea
  • Grade 3/4 laboratory abnormalities included neutropenia (29%), thrombocytopenia (22%), anemia (13%), hypophosphatemia (7%), hypocalcemia (4%), elevated bilirubin (1%), and elevated creatinine (1%)
• In adult patients resistant or intolerant to prior imatinib therapy:
  • Drug-related SARs were reported for 26.1% of DASATINIB-treated patients treated at the recommended dose of 100 mg once daily in the randomized dose-optimization trial of patients with chronic phase CML resistant or intolerant to prior imatinib therapy. Serious adverse reactions reported in ≥5% of patients included pleural effusion (10%)
  • The most common adverse reactions (≥15%) included myelosuppression, fluid retention events, headache, diarrhea, fatigue, dyspnea, musculoskeletal pain, nausea, hemorrhage and skin rash
  • Grade 3/4 hematologic laboratory abnormalities in chronic phase CML patients resistant or intolerant to prior imatinib therapy who received DASATINIB 100 mg once daily with a minimum follow up of 60 months included neutropenia (36%), thrombocytopenia (24%), and anemia (13%). Other grade 3/4 laboratory abnormalities included: hypophosphatemia (10%), and hypokalemia (2%)
• Grade 3/4 elevations of transaminases or bilirubin and Grade 3/4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML
  • Elevations in transaminases or bilirubin were usually managed with dose reduction or interruption
  • Patients developing Grade 3/4 hypocalcemia during the course of DASATINIB therapy often had recovery with oral calcium supplementation



In a multicohort study of DASATINIB administered continuously in combination with multiagent chemotherapy in 81 pediatric patients with newly diagnosed Ph+ ALL, the median duration of therapy was 24 months (range 2 to 27 months).

• In pediatric subjects with Ph+ ALL who were administered DASATINIB in combination with multiagent chemotherapy:
  • Fatal adverse reactions occurred in 3 patients (4%), all of which were due to infections
  • Eight patients (10%) experienced adverse reactions leading to treatment discontinuation
  • The most common serious adverse reactions (incidence ≥10%) were pyrexia, febrile neutropenia, mucositis, diarrhea, sepsis, hypotension, infections (bacterial, viral and fungal), hypersensitivity, vomiting, renal insufficiency, abdominal pain, and musculoskeletal pain
  • The most common adverse reactions (≥30%) in pediatric patients receiving DASATINIB in combination with chemotherapy included mucositis, febrile neutropenia, pyrexia, diarrhea, nausea, vomiting, musculoskeletal pain, abdominal pain, cough, headache, rash, fatigue, constipation, arrhythmia, hypertension, edema, infections (bacterial, viral and fungal), hypotension, decreased appetite, hypersensitivity, dyspnea, epistaxis, peripheral neuropathy, and altered state of consciousness
  • Grade 3/4 laboratory abnormalities (≥10%) included neutropenia (96%), thrombocytopenia (88%), anemia (82%), elevated SGPT (ALT) (47%), hypokalemia (40%), elevated SGOT (AST) (26%), hypocalcemia (19%), hyponatremia (19%), elevated bilirubin (11%), and hypophosphatemia (11%)



In two non-randomized trials in 97 pediatric patients with chronic phase CML (51 patients newly diagnosed and 46 patients resistant or intolerant to previous treatment with imatinib), the median duration of therapy was 51.1 months (range 1.9 to 99.6 months).

• Among the 97 CML pediatric subjects, drug-related adverse reactions leading to discontinuation were reported in 1 patient (1%)
• Drug-related serious adverse reactions were reported for 14.4% of pediatric patients
• Adverse reactions associated with bone growth and development were reported in 5 (5.2%) of pediatric patients with chronic phase CML
• The most common adverse reactions (≥15%) in pediatric patients included myelosuppression, headache, nausea, diarrhea, skin rash, pain in extremity, and abdominal pain.



Please see full Prescribing Information (20/50/70/100 mg or 80/140 mg) and Patient Information (20/50/70/100 mg or 80/140 mg) for DASATINIB TABLETS corresponding to the specific dosage form.